The Only Hydroxychloroquine Story You Need to Read
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
In the early days of a pandemic caused by a virus with no existing treatments, many different compounds are often considered and tried in an attempt to help patients.
It all relates back to a profound question: How do we know what we know?
Many of these treatments fall by the wayside as evidence accumulates regarding actual efficacy. At that point, other treatments become standard of care once their benefit is proven in rigorously designed trials.
However, about seven months into the pandemic, we're still seeing political resurrection of a treatment that has been systematically studied and demonstrated in well-designed randomized controlled trials to not have benefit.
The hydroxychloroquine (and by extension chloroquine) story is a complicated one that was difficult to follow even before it became infused with politics. It is a simple fact that these drugs, long approved by the Food and Drug Administration (FDA), work in Petri dishes against various viruses including coronaviruses. This set of facts provided biological plausibility to support formally studying their use in the clinical treatment and prevention of COVID-19. As evidence from these studies accumulates, it is a cognitive requirement to integrate that knowledge and not to evade it. This also means evaluating the rigor of the studies.
In recent days we have seen groups yet again promoting the use of hydroxychloroquine in, what is to me, a baffling disregard of the multiple recent studies that have shown no benefit. Indeed, though FDA-approved for other indications like autoimmune conditions and preventing malaria, the emergency use authorization for COVID-19 has been rescinded (which means the government cannot stockpile it). Still, however, many patients continue to ask for the drug, compelled by political commentary, viral videos, and anecdotal data. Yet most doctors (like myself) are refusing to write the prescriptions outside of a clinical trial – a position endorsed by professional medical organizations such as the American College of Physicians and the Infectious Diseases Society of America. Why this disconnect?
It all relates back to a profound question: How do we know what we know? In science, we use the scientific method – the process of observing reality, coming up with a hypothesis about what might be true, and testing that hypothesis as thoroughly as possible until we discover the objective truth.
The confusion we're seeing now stems from an inability to distinguish between anecdotes reported by physicians (observational data) and an actual evidence base. This is understandable among the general public but when done by a healthcare professional, it reveals a disdain for reason, logic, and the scientific method.
The Difference Between Observational Data and Randomized Controlled Trials
The power of informal observation is crucial. It is part of the scientific method but primarily as a basis for generating hypotheses that we can test. How do we conduct medical tests? The gold standard is the double-blind, randomized, placebo-controlled trial. This means that neither the researchers nor the volunteers know who is getting a drug and who is getting a sugar pill. Then both groups of the trial, called arms, can be compared to determine whether the people who got the drug fared better. This study design prevents biases and the placebo effect from confounding the data and undermining the veracity of the results.
For example, a seemingly beneficial effect might be seen in an observational study with no blinding and no control group. In such a case, all patients are openly given the drug and their doctors observe how they do. A prime example is the 36-patient single-arm study from France that generated a tremendous amount of interest after President Trump tweeted about it. But this kind of a study by its nature cannot answer the critical question: Was the positive effect because of hydroxychloroquine or just the natural course of the illness? In other words, would someone have recovered in a similar fashion regardless of the drug? What is the role of the placebo effect?
These are reasons why it is crucial to give a placebo to a control group that is as similar in every respect as possible to those receiving the intervention. Then we attempt to find out by comparing the two groups: What is the side effect profile of the drug? Are the groups large enough to detect a relatively rare safety concern? How long were the patients followed for? Was something else responsible for making the patients get better, such as the use of steroids (as likely was the case in the Henry Ford study)?
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur.
All of these considerations amount to just a fraction of the questions that can be answered more definitively in a well-designed large randomized controlled trial than in observational studies. Indeed, an observational study from New York failed to show any benefit in hospitalized patients, showing how unclear and disparate the results can be with these types of studies. A New York retrospective study (which examined patient outcomes after they were already treated) had similar results and included the use of azithromycin.
When evaluating a study, it is also important to note whether conflicts of interest exist, as well as the quality of the peer review and the data itself. In the case of the French study, for example, the paper was published in a journal in which one of the authors was editor-in-chief, and it was accepted for publication after 24 hours. Patients who fared poorly on hydroxychloroquine were also left out of the study altogether, skewing the results.
What Randomized Controlled Trials Have Shown
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur. The most important of these studies to announce results was part of the Recovery trial, which was designed to test multiple interventions in the treatment of COVID-19. This trial, which has yet to be formally published, was a randomized controlled trial that involved over 1500 hospitalized patients being administered hydroxychloroquine compared to over 3000 who did not receive the medication. Clinical testing requires large numbers of patients to have the power to demonstrate statistical significance -- the threshold at which any apparent benefit is more than you would expect by random chance alone.
In this study, hydroxychloroquine provided no mortality benefit or even a benefit in hospital length of stay. In fact, the opposite occurred. Hydroxychloroquine patients were more likely to stay in the hospital longer and were more likely to require mechanical ventilation. Additionally, smaller randomized trials conducted in China have not shown benefit either.
Another major study involved the use of hydroxychloroquine to prevent illness in people who were exposed to COVID-19. These results, published in The New England Journal of Medicine, included over 800 patients who were studied in a randomized double-blind controlled trial and also failed to show any benefit.
But what about adding the antibiotic azithromycin in conjunction with hydroxychloroquine? A three-arm randomized controlled study involving over 500 patients hospitalized with mild to moderate COVID-19 was conducted. Its results, also published in The New England Journal of Medicine, failed to show any benefit – with or without azithromycin – and demonstrated evidence of harm. Those who received these treatments had elevations of their liver function tests and heart rhythm abnormalities. These findings hold despite the retraction of an observational study showing similar results.
Additionally, when used in combination with remdesivir – an experimental antiviral – hydroxychloroquine has been shown to be associated with worse outcomes and more side effects.
But what about in mildly ill patients not requiring hospitalization? There was no benefit found in a randomized double-blind placebo-controlled trial of 400 patients, the majority of whom were given the drug within one day of symptoms.
Some randomized controlled studies have yet to report their findings on hydroxychloroquine in non-hospitalized patients, with the use of zinc (which has some evidence in the treatment of the common cold, another ailment that can be caused by coronaviruses). And studies have yet to come out regarding whether hydroxychloroquine can prevent people from getting sick before they are even exposed. But the preponderance of the evidence from studies designed specifically to find benefit for treating COVID-19 does not support its use outside of a research setting.
Today – even with some studies (including those with zinc) still ongoing – if a patient asked me to prescribe them hydroxychloroquine for any severity or stage of illness, with or without zinc, with or without azithromycin, I would refrain. I would explain that, based on the evidence from clinical trials that has been amassed, there is no reason to believe that it will alter the course of illness for the better.
Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
What has been occurring is a continual shifting of goalposts with each negative hydroxychloroquine study. Those in favor of the drug protest that a trial did not include azithromycin or zinc or wasn't given at the right time to the right patients. While there may be biological plausibility to treating illness early or combining treatments with zinc, it can only be definitively shown in a randomized, controlled prospective study.
The bottom line: A study that only looks at past outcomes in one group of patients – even when well conducted – is at most hypothesis generating and cannot be used as the sole basis for a new treatment paradigm.
Some may argue that there is no time to wait for definitive studies, but no treatment is benign. The risk/benefit ratio is not the same for every possible use of the drug. For example, hydroxychloroquine has a long record of use in rheumatoid arthritis and systemic lupus (whose patients are facing shortages because of COVID-19 related demand). But the risk of side effects for many of these patients is worth taking because of the substantial benefit the drug provides in treating those conditions.
In COVID-19, however, the disease apparently causes cardiac abnormalities in a great deal of many mild cases, a situation that should prompt caution when using any drugs that have known effects on the cardiac system -- drugs like hydroxychloroquine and azithromycin.
My Own Experience
It is not the case that every physician was biased against this drug from the start. Indeed, most of us wanted it to be shown to be beneficial, as it was a generic drug that was widely available and very familiar. In fact, early in the pandemic I prescribed it to hospitalized patients on two occasions per a hospital protocol. However, it is impossible for me as a sole clinician to know whether it worked, was neutral, or was harmful. In recent days, however, I have found the hydroxychloroquine talk to have polluted the atmosphere. One recent patient was initially refusing remdesivir, a drug proven in large randomized trials to have effectiveness, because he had confused it with hydroxychloroquine.
Moving On to Other COVID Treatments: What a Treatment Should Do
The story of hydroxychloroquine illustrates a fruitless search for what we are actually looking for in a COVID-19 treatment. In short, we are looking for a medication that can decrease symptoms, decrease complications, hasten recovery, decrease hospitalizations, decrease contagiousness, decrease deaths, and prevent infection. While it is unlikely to find a single antiviral that can accomplish all of these, fulfilling even just one is important.
For example, remdesivir hastens recovery and dexamethasone decreases mortality. Definitive results of the use of convalescent plasma and immunomodulating drugs such as siltuxamab, baricitinib, and anakinra (for use in the cytokine storms characteristic of severe disease) are still pending, as are the trials with monoclonal antibodies.
While it was crucial that the medical and scientific community definitively answer the questions surrounding the use of chloroquine and hydroxychloroquine in the treatment of COVID-19, it is time to face the facts and accept that its use for the treatment of this disease is not likely to be beneficial. Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on new scientific theories and progress to give you a therapeutic dose of inspiration headed into the weekend.
This episode includes an interview with Dr. Helen Keyes, Head of the School of Psychology and Sports Science at Anglia Ruskin University.
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As a graduate student in observational astronomy at the University of Arizona during the 1970s, Diane Turnshek remembers the starry skies above the Kitt Peak National Observatory on the Tucson outskirts. Back then, she could observe faint objects like nebulae, galaxies, and star clusters on most nights.
When Turnshek moved to Pittsburgh in 1981, she found it almost impossible to see a clear night sky because the city’s countless lights created a bright dome of light called skyglow. Over the next two decades, Turnshek almost forgot what a dark sky looked like. She witnessed pristine dark skies in their full glory again during a visit to the Mars Desert Research Station in Utah in early 2000s.
“I was shocked at how beautiful the dark skies were in the West. That is when I realized that most parts of the world have lost access to starry skies because of light pollution,” says Turnshek, an astronomer and lecturer at Carnegie Mellon University. In 2015, she became a dark sky advocate.
Light pollution is defined as the excessive or wasteful use of artificial light.
Light-emitting diodes (LEDs) -- which became commercially available in 2002 and rapidly gained popularity in offices, schools, and hospitals when their price dropped six years later — inadvertently fueled the surge in light pollution. As traditional light sources like halogen, fluorescent, mercury, and sodium vapor lamps have been phased out or banned, LEDs became the main source of lighting globally in 2019. Switching to LEDs has been lauded as a win-win decision. Not only are they cheap but they also consume a fraction of electricity compared to their traditional counterparts.
But as cheap LED installations became omnipresent, they increased light pollution. “People have been installing LEDs thinking they are making a positive change for the environment. But LEDs are a lot brighter than traditional light sources,” explains Ashley Wilson, director of conservation at the International Dark-Sky Association (IDA). “Despite being energy-efficient, they are increasing our energy consumption. No one expected this kind of backlash from switching to LEDs.”
Light pollution impacts the circadian rhythms of all living beings — the natural internal process that regulates the sleep–wake cycle.
Currently, more than 80 percent of the world lives under light-polluted skies. In the U.S. and Europe, that figure is above 99 percent.
According to the IDA, $3 billion worth of electricity is lost to skyglow every year in the U.S. alone — thanks to unnecessary and poorly designed outdoor lighting installations. Worse, the resulting light pollution has insidious impacts on humans and wildlife — in more ways than one.
Disrupting the brain’s clock
Light pollution impacts the circadian rhythms of all living beings—the natural internal process that regulates the sleep–wake cycle. Humans and other mammals have neurons in their retina called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells collect information about the visual world and directly influence the brain’s biological clock in the hypothalamus.
The ipRGCs are particularly sensitive to the blue light that LEDs emit at high levels, resulting in suppression of melatonin, a hormone that helps us sleep. A 2020 JAMA Psychiatry study detailed how teenagers who lived in areas with bright outdoor lighting at night went to bed late and slept less, which made them more prone to mood disorders and anxiety.
“Many people are skeptical when they are told something as ubiquitous as lights could have such profound impacts on public health,” says Gena Glickman, director of the Chronobiology, Light and Sleep Lab at Uniformed Services University. “But when the clock in our brains gets exposed to blue light at nighttime, it could result in a lot of negative consequences like impaired cognitive function and neuro-endocrine disturbances.”
In the last 12 years, several studies indicated that light pollution exposure is associated with obesity and diabetes in humans and animals alike. While researchers are still trying to understand the exact underlying mechanisms, they found that even one night of too much light exposure could negatively affect the metabolic system. Studies have linked light pollution to a higher risk of hormone-sensitive cancers like breast and prostate cancer. A 2017 study found that female nurses exposed to light pollution have a 14 percent higher risk of breast cancer. The World Health Organization (WHO) identified long-term night shiftwork as a probable cause of cancer.
“We ignore our biological need for a natural light and dark cycle. Our patterns of light exposure have consequently become different from what nature intended,” explains Glickman.
Circadian lighting systems, designed to match individuals’ circadian rhythms, might help. The Lighting Research Center at Rensselaer Polytechnic Institute developed LED light systems that mimic natural lighting fluxes, required for better sleep. In the morning the lights shine brightly as does the sun. After sunset, the system dims, once again mimicking nature, which boosts melatonin production. It can even be programmed to increase blue light indoors when clouds block sunlight’s path through windows. Studies have shown that such systems might help reduce sleep fragmentation and cognitive decline. People who spend most of their day indoors can benefit from such circadian mimics.
When Diane Turnshek moved to Pittsburgh, she found it almost impossible to see a clear night sky because the city’s countless lights created a bright dome of light called skyglow.
Diane Turnshek
Leading to better LEDs
Light pollution disrupts the travels of millions of migratory birds that begin their long-distance journeys after sunset but end up entrapped within the sky glow of cities, becoming disoriented. A 2017 study in Nature found that nocturnal pollinators like bees, moths, fireflies and bats visit 62 percent fewer plants in areas with artificial lights compared to dark areas.
“On an evolutionary timescale, LEDs have triggered huge changes in the Earth’s environment within a relative blink of an eye,” says Wilson, the director of IDA. “Plants and animals cannot adapt so fast. They have to fight to survive with their existing traits and abilities.”
But not all types of LEDs are inherently bad -- it all comes down to how much blue light they emit. During the day, the sun emits blue light waves. By sunset, red and orange light waves become predominant, stimulating melatonin production. LED’s artificial blue light, when shining at night, disrupts that. For some unknown reason, there are more bluer color LEDs made and sold.
“Communities install blue color temperature LEDs rather than redder color temperature LEDs because more of the blue ones are made; they are the status quo on the market,” says Michelle Wooten, an assistant professor of astronomy at the University of Alabama at Birmingham.
Most artificial outdoor light produced is wasted as human eyes do not use them to navigate their surroundings.
While astronomers and the IDA have been educating LED manufacturers about these nuances, policymakers struggle to keep up with the growing industry. But there are things they can do—such as requiring LEDs to include dimmers. “Most LED installations can be dimmed down. We need to make the dimmable drivers a mandatory requirement while selling LED lighting,” says Nancy Clanton, a lighting engineer, designer, and dark sky advocate.
Some lighting companies have been developing more sophisticated LED lights that help support melatonin production. Lighting engineers at Crossroads LLC and Nichia Corporation have been working on creating LEDs that produce more light in the red range. “We live in a wonderful age of technology that has given us these new LED designs which cut out blue wavelengths entirely for dark-sky friendly lighting purposes,” says Wooten.
Dimming the lights to see better
The IDA and advocates like Turnshek propose that communities turn off unnecessary outdoor lights. According to the Department of Energy, 99 percent of artificial outdoor light produced is wasted as human eyes do not use them to navigate their surroundings.
In recent years, major cities like Chicago, Austin, and Philadelphia adopted the “Lights Out” initiative encouraging communities to turn off unnecessary lights during birds’ peak migration seasons for 10 days at a time. “This poses an important question: if people can live without some lights for 10 days, why can’t they keep them turned off all year round,” says Wilson.
Most communities globally believe that keeping bright outdoor lights on all night increases security and prevents crime. But in her studies of street lights’ brightness levels in different parts of the US — from Alaska to California to Washington — Clanton found that people felt safe and could see clearly even at low or dim lighting levels.
Clanton and colleagues installed LEDs in a Seattle suburb that provided only 25 percent of lighting levels compared to what they used previously. The residents reported far better visibility because the new LEDs did not produce glare. “Visual contrast matters a lot more than lighting levels,” Clanton says. Additionally, motion sensor LEDs for outdoor lighting can go a long way in reducing light pollution.
Flipping a switch to preserve starry nights
Clanton has helped draft laws to reduce light pollution in at least 17 U.S. states. However, poor awareness of light pollution led to inadequate enforcement of these laws. Also, getting thousands of counties and municipalities within any state to comply with these regulations is a Herculean task, Turnshek points out.
Fountain Hills, a small town near Phoenix, Arizona, has rid itself of light pollution since 2018, thanks to the community's efforts to preserve dark skies.
Until LEDs became mainstream, Fountain Hills enjoyed starry skies despite its proximity to Phoenix. A mountain surrounding the town blocks most of the skyglow from the city.
“Light pollution became an issue in Fountain Hills over the years because we were not taking new LED technologies into account. Our town’s lighting code was antiquated and out-of-date,” says Vicky Derksen, a resident who is also a part of the Fountain Hills Dark Sky Association founded in 2017. “To preserve dark skies, we had to work with the entire town to update the local lighting code and convince residents to follow responsible outdoor lighting practices.”
Derksen and her team first tackled light pollution in the town center which has a faux fountain in the middle of a lake. “The iconic centerpiece, from which Fountain Hills got its name, had the wrong types of lighting fixtures, which created a lot of glare,” adds Derksen. They then replaced several other municipal lighting fixtures with dark-sky-friendly LEDs.
The results were awe-inspiring. After a long time, residents could see the Milky Way with crystal clear clarity. Star-gazing activities made a strong comeback across the town. But keeping light pollution low requires constant work.
Derksen and other residents regularly measure artificial light levels in
Fountain Hills. Currently, the only major source of light pollution is from extremely bright, illuminated signs which local businesses had installed in different parts of the town. While Derksen says it is an uphill battle to educate local businesses about light pollution, Fountain Hills residents are determined to protect their dark skies.
“When a river gets polluted, it can take several years before clean-up efforts see any tangible results,” says Derksen. “But the effects are immediate when you work toward reducing light pollution. All it requires is flipping a switch.”